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REGISTRIES TRACK IMPACT OF ANTIEPILEPTICS IN PREGNANCY

NEW ORLEANS — Researchers are trying to develop registries that will give doctors and patients clues to decide which antiepileptic drugs are appropriate for controlling seizures in the mother-to-be and in preventing increased risk of developmental problems in the newborns.

“As more and more antiepileptics are brought to the market, we need to know which of these medications are suitable in pregnancy,” said Mark Yerby, MD, Associate Professor of Neurology, Public Health, and Obstetrics and Gynecology at the Oregon Health Sciences University in Portland.

This is why, Dr. Yerby said, he hoped that doctors and patients would enroll in wide-spectrum registries such as the North American Registry, which includes a control group and allows for some comparisons among drugs.

Dr. Georgia Montouris, MD, Assistant Professor of Neurology at Boston University in Massachusetts, who is participating in the levetiracetam (Keppra) Pregnancy Registry, said that in addition to monitoring patients for adverse pregnancy outcomes, the registries will also provide considerable other information for doctors.

“An estimated 30 percent of women with epilepsy experience exacerbation of seizures during pregnancy,” Dr. Montouris said, “and seizures may have a greater impact on the developing fetus than medications.” She said the registries will be able to demonstrate how well seizures are controlled by individual drugs. And, she said, if a drug for some reason or another is not optimal for use in pregnancy, the drugs still may be useful in men or in women who do not have child-bearing potential.

VALPROATE AND TERATOGENICITY

At the Annual Meeting of the American Epilepsy Society here in December, several doctors reported that studies indicate treatment of pregnant epileptic women with sodium valproate or phenobarbital tends to increase the risk of developmental problems in newborns.

Lewis Holmes, MD, Professor of Pediatrics at Harvard Medical School in Boston, said in a press briefing that seven different registries all found that valproate was most often cited by women who had taken medication for epilepsy while pregnant.

“Maternal exposure to valproate during the first trimester of pregnancy significantly increases teratogenicity in humans,” Dr. Holmes said. “When consulting with women of childbearing age, the risk of teratogenicity should be an important factor in selecting therapy.”

In one of his studies, he noted that about 11 percent of women exposed to valproate in utero produced children with congenital malformations, while about 2.9 percent of women receiving other antiepileptics had children with abnormalities. The difference was statistically significant at the p<0.001 level, he said.

Kimford Meador, MD, the Melvin Greer Professor of Neurology at the University of Florida in Gainesville, noted that a United Kingdom registry found that as many as 30 percent of children exposed to valproate monotherapy in utero experienced the risk of requiring additional educational – compared with 6.5 percent or less for children whose mothers took other antiepileptics.

“Each study has limitations,” Dr. Meador said, “but together they suggest there is a great risk for valproate.”

“The evidence suggests that valproate and phenobarbital should not be first-line treatments for women who are pregnant and have epilepsy,” Dr. Montouris said. But she noted that 92 to 96 percent of women on antiepileptic drugs of any kind have normal pregnancies and deliver normal, healthy babies.

CHANGING THERAPY DURING PREGNANCY

“Because seizures are a greater risk to the outcome of a pregnancy, doctors and patients have to weigh the decision to change drugs during pregnancy – if a woman is well-controlled on a particular drug,” she said.

For example, Dr. Montouris said a clinician would have a difficult decision if he or she was already treating a woman with valproate and the woman became pregnant. The question is whether a “safer” drug for the developing fetus might be less effective and might permit seizures that could be as damaging as, or more damaging than, the drug to the fetus.

“That is really a question to be asked prior to pregnancy,” said Dr. Yerby. The effects of valproate on pregnancy usually occur in the first trimester, he said, and that period might be concluded by the time a woman realizes she is pregnant.

The single drug registries – such as those for lamotrigine and levetiracetam – have been developed already, Dr. Yerby said, because most of these newer drugs get approval from the Food and Drug Administration as “add-on” medications and are not often used as monotherapy in early marketing.

If a patient is using polypharmacy it might be difficult to tease out which drug is causing a problem in pregnancy and childbirth. But because the newer drugs will not be used frequently as monotherapy in pregnant women, the registries will have to record these cases as they come to determine the safety of each medication.

Dr. Montouris said that researchers will have to record prospectively about 400 patients on the monotherapy product during pregnancy for doctors to get a decent handle on what – if any – problems the drugs cause during pregnancy.

Another epilepsy expert, who was not involved in these studies, stressed the importance of the registries. “These registries are important because they have the potential to tell us which drugs are best for out patients and which ones require caution,” said Gregory Barkley, MD, Assistant Professor of Neurology at Wayne State University in Detroit, MI.

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